The long-term goals of this ongoing project are to investigate membrane lipid composition and turnover in peripheral nerve and platelets, to define and measure lipid metabolic alterations induced by chronic diabetes, to correlate these alterations with structural and functional parameters of diabetic neuropathy, and to determine potential regulatory mechanisms in nerve lipid metabolism. We will correlate lipid compositional and metabolic alterations in diabetic rat sciatic nerve with structural and functional alterations (Aim 1). These studies will involve the uptake and utilization of labeled lipid precursors by endoneurial segments of normal and diabetic rat sciatic nerve, together with ultrastructural and functional evaluations of these nerves, and will include experiments aimed at detecting lipid degradation products formed upon incubation of prelabeled nerves. Diabetes will be induced by streptozotocin or alloxan injections with and without subsequent insulin treatment. Spontaneous autoimmune diabetes in the BB Wistar rat will also be utilized. The enzymes of inositol phospholipid metabolism, i.e., kinases, phosphomonoesterases, and phosphodiesterases. Phospholipases A1, A2, lysophospholipases, acyltransferases, and transacylases will be characterized and comparisons will be made between enzyme activities of normal and diabetic nerve (Aim 2). We also propose to investigate the effects of lithium on nerve lipid metabolism and nerve function and to continue studies on the effects of Wallerian degeneration and regeneration on phospholipid metabolism with special emphasis on phosphatidyinositol and the polyphosphoinositides (Aim 3). The uptake of polyunsaturated fatty acids into membrane phospholipids, their transfer between and release from phospholipids will be investigated in both peripheral nerve and platelets. Conversion of arachidonic acid by cyclooxygenase and lipoxygenase activity will be determined with preparations of rat sciatic nerve.